The macula is a unique and highly specialized region of the primate retina. It contains the highest densities of rod and cone photoreceptor cells and encompasses the cone-enriched fovea, which mediates high acuity central vision. Unfortunately, loss of central vision is a significant consequence of various retinal degenerations, including cone-rod dystrophies and macular degenerations. For example, vision loss in age-related macular degeneration (AMD), is responsible for about one-half of all registered blindness in the Western world. These degenerations are characterized by dysfunction and, ultimately, death of rod and cone photoreceptors and the overlying retinal pigment epithelial (RPE) cells in the macula. Previous studies have suggested that perifoveal rod photoreceptor loss precedes that of cones in AMD; however, our understanding of the mechanism of macular and foveal cone loss in this process is poor. It appears that cones, especially foveal cones, have a capacity for survival in a region of the retina that has a propensity for degeneration. To understand the functional role of macular and foveal cones in the homeostasis of the normal retina and in the pathobiology of the diseased retina, we believe that it is critical to define the molecular "fingerprint" of these cells. We hypothesize that differential gene expression by foveal cones defines the unique microenvironment of the macula, including the fovea. Furthermore, some of these genes may contribute to disease susceptibility while others may enhance photoreceptor survival. Thus, the following aims are proposed: (1) Identify genes preferentially expressed in the primate fovea. (2) Characterize fovea-associated/cone-specific genes and identify the proteins they encode. (3) Determine the functional roles of fovea-associated proteins. The central theme of our research program is that differential gene expression in the central millimeter of primate retina (in foveal cone photoreceptors) impacts on the pathology of macular degenerations. Understanding normal foveal cone biology and its alteration in disease will provide the rationale for therapies to prolong photoreceptor survival in macular degeneration.